C. albicans normally resides in the gastrointestinal tract of healthy individuals as harmless, commensal yeast. Conditions that cause defects in cell mediated immunity, and/or deficiencies in neutrophils and loss of mucosal barrier function allow C. albicans to over grow, cause mucosal disease such as oropharyngeal candidiasis (OPC) , or enter the blood stream, and cause disseminated infection. C. albicans-host mucosal interactions are thus of primary importance in mediating risks for both OPC and invasive disease. Previously we identified a C. albicans protein, Hyphal Wall Protein 1 (Hwp1), which mediates a unique interaction between C. albicans filamentous cells and the surface of buccal epithelial cells (BECs). This interaction is in the form of a covalent bond between Hwp1 and an unidentified BEC surface co-substrate protein, catalyzed by a member of the family of transglutaminases (TGs). We also determined that Hwp1 was needed for systemic candidiasis in the intravenous mouse model, but the role of the fungal protein in this infection model was not revealed. The long- term goal of this research is to better understand how the adhesin and virulence factor, Hwp1, is involved C. albicans' ability to interact with host cells. This proposal is based on the hypothesis that host TG-mediated reactions that utilize Hwp1 as a substrate are essential for mucosal and disseminated candidiasis. The Aims of this proposal are: (1) To determine the identity of the host lysine donor proteins that participate with Hwp1 in stabilized adhesion to epithelial and endothelial cell surfaces. (2) To determine the role of Hwp1 in translocation of C. albicans across the intestinal mucosa. (3) To determine the role of TG2 in disseminated candidiasis. The aims proposed here will provide insights into the mechanism of fungal-host interactions that can lead to disease. Further understanding of candidiasis has the potential to generate improved disease management strategies.